N-pyridylalkyl-{62 -alkoxy-{62 -trifluoromethyl-phenalkylamines

ABSTRACT

N-Pyridylalkyl- Beta -alkoxy- Beta trifluoromethylphenalkylamines having anorectic activity are prepared by the condensation of an N-pyridylalkylamine with a Beta -alkoxytrifluoromethylphenakyl halide.

United States Patent Ross et al.

[451 July 25,1972

N-PYRIDYLALKYL-B-ALKOXY-B- TRIFLUOROMETHYL- PHENALKYLAMINES Stephen T.Ross; Charles L. Zirkle, both of Berwyn, Pa.

Smith Kline 8: French Laboratories, Philadelphia, Pa.

Filed: Sept. 15, 1970 Appl. No.: 72,536

Inventors:

Assignee:

US. Cl. ..260/296 AE, 260/294.8 R, 260/295 S,

424/263, 424/266 Int. Cl. C07d 31/42 Field of Search ..260/296 R, 296AB, 296 S, 294.8

Primary Examiner-Alan L. Rotman Attorney-William H. Edgerton, Richard D.Foggio, Joan S. Keps, Alan D. Lourie and Joseph A. Marlino [57] ABSTRACTN-Pyridylalkyl-B-alkoxy-B-trifluoromethylphenalkylamines havinganorectic activity are prepared by the condensation of anN-pyridylalkylamine with a B-alkoxytrifluoromethylphenakyl halide.

8 Claims, No Drawings N-PYRlDYLALKYbfl-ALKOXY-B-TRIFLUOROMETHYLPHENALKYLAMINES This invention relates to novelN-pyridylalkyl-fl-alkoxytrifluoromethylphenalkylamines which have usefulpharmacodynarnic activity. More specifically, these compounds haveutility as anorectic agents, that is, they produce a significantdecrease in body weight gain accompanied by anorexia with little or noside effects.

The compounds of this invention may be represented by the followingstructural formula:

-m qz s I in which R represents lower alkyl of from one to three carbonatoms,

preferably methyl; R, represents hydrogen or methyl; R representshydrogen or lower alkyl of from one to three carbon atoms; and Arepresents a lower alkylene chain, straight or branched,

of from one to three carbon atoms. Preferred compounds of this inventionare represented by the following structural formula:

Forrnula II in which R and R are each hydrogen or methyl.

The compounds of this invention may be used in the form of apharmaceutically acceptable acid addition salt having the utility of thefree base. Such salts, prepared by methods well known to the art, areformed with both inorganic or organic acids, for example: maleic,fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicyclic,methane-sulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic,citraconic, aspartic, stearic, palmitic, itaconic, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic,sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.

A convenient method for the preparation of the compounds of thisinvention is illustrated by the following reaction:

in which R, R R and A are as defined above for formula I and X ishalogen. Thus, when R is lower alkyl, a trifluoromethyl substitutedB-alkoxyphenalkyl halide, preferably bromide, is condensed with anN-alkyl-N-pyridylalkylamine in a nonreactive organic solvent such asbenzene, toluene or xylene, in the presence of an alkali metalcarhonate, for example potassium carbonate, at reflux temperature forfrom 4 to 12 hours. When R is hydrogen, the phenalkyl halide isadvantageously condensed with an excess of the N-pyridylalkylamine atabout 80 to 120 C. for from I to 3 hours.

Racemic mixtures of the compounds of this invention are obtained by thismethod of preparation as a result of the asymmetric substitution of oneor more carbon atoms. Such mixtures can be resolved by fractionalcrystallization of an optically active salt of the amine product. Unlessotherwise stated herein it is intended to include in the structuralformulas and in the claims, both the racemic mixtures as well as theseparated a and l isomers.

The preparation of the appropriately substituted B-alkoxyphenalkylhalides used as starting materials herein is described in US. Pat Nos.3,226,440 and 3,459,803.

The anorectic activity of the compounds of this invention isdemonstrated by a standard pharmacological procedure as follows.Compounds are tested orally for their ability to quantitatively reducefirst hour food consumption of rats trained to consume their daily foodrequirements in only 6 hours. A preferred compound of this invention,N-( 3-pyridylmethyl)-{3 -methoxy-B-(3-trifluoromethylphenyl)-ethylamine,has an oral anorectic ED in rats of 4.4 mg/kg.

To obtain anorectic activity the compounds of this invention areadvantageously administered orally or parenterally to an animal organismin conventional dosage unit forms, Preferably a compound or an acidaddition salt thereof is administered orally in a tablet or capsule. Thedosage units are prepared by incorporating the active medicament in anamount sufiicient to produce anorectic activity with a nontoxicpharmaceutical carrier according to accepted procedures. Preferably eachdosage unit will contain the active medicament in an amount of about 10mg. to about 100 mg. Advantageously equal doses will be administered twoto four times daily with the daily dosage regimen being about 20 mg. toabout 400 mg.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly the carrier or diluent can includeany time delay material well known to the art, such as glycerylmonstearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be about 25 mg. to about 1 g. If a liquid carrier is used, thepreparation will be in the form of a syrup,'emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule, or an aqueous ornonaqueous liquid suspension.

The following examples illustrate more specifically how to preparecompounds of this invention. However, as such, they are not to beconstrued as limiting the scope of the invention as defined in formulasI and II above.

EXAMPLE 1 A mixture of 51.0 g. (0.180 m.) of B-methoxy-fi-( 3-trifluoromethylphenyl)-ethyl bromide and 58.4 g. (0.540 m.) of3-aminomethylpyridine is stirred and heated to C. under nitrogen for 2hours. The cooled reaction mixture is diluted with water, excesshydrochloric acid is added and the mixture is extracted with ether. Theaqueous layer is made basic with concentrated ammonium hydroxide andreextracted with ether. The dried ether extract is concentrated and theresidue vacuum distilled to giveB-methoxy-B-(Ii-trifluoromethylphenyl)-N-( 3 '-pyridylmethyl)-ethylamine, b.p. l37.5-l 53 C./0. 10 mm.; hydrochloride, m.p. l56l 59C.

Similarly, reaction of 3-aminomethylpyridine with B-ethoxy-[3-(3-trifluoromethylphenyl)-ethyl bromide as described above yieldsB-ethoxy-B-(3-trifiuoromethylphenyl)-N-(3- pyridylmethyl)-ethylamine.

EXAMPLE 2 A mixture of 10.06 g. (0.0820 m.) ofN-methyl-S-pyridylmethylamine, 38 ml. of xylene, 5.66 g. (0.0410 m.) ofpotassium carbonate and 23.20 g. (0.0820 m.) of fl-methoxy-p-(3-trifluotomethylphenyD-ethyl bromide is stirred at reflux 148 C.) for H2hours. The cooled reaction mixture is filtered and the filtrateconcentrated under reduced pressure. The residue is vacuum distilled togive fi-methoxy-N-methyl-N-(3'-pyridylmethyl)-B-(3-trifluoromethylphenyl)-ethylamine, ll8.5-l48 C./0.05 mm.; hexamate,m.p. ll5-l 18 C.

EXAMPLE 3 fi-Methoxy-fi-(3'-trifluoromethylphenyl)-ethyl bromide (25.0g., 0.0884 m.) and 28.6 g. (0.2652 m.) of 2- aminomethylpyridine arestirred and heated at 80 C. under nitrogen for one hour. The cooledreaction mixture is partitioned between water and ether, excess ammoniumhydroxide is added and the aqueous phase is extracted with ether. Theether extract is concentrated to an oily residue which is vacuumdistilled to yield fi-methoxy-N-'(2'-pyridylmethyl)-B-(S-trifluoromethylphenyl)-ethylamine, b./. ll7l26 C./0.l0

mm.; hydrochloride, m.p. 132-l 36 C.

EXAMPLE 4 l28l 38 C./0. mm.; hydrochloride, m.p. 224.5-228.5 C.-

EXAMPLE 5 Following the procedure of Example 1, B-aminomethylpyridine isreacted with B-methoxy-fi-(2-trifluoromethylphenyl)-ethyl bromide toyield )8-methoxy-B-( 2-trifluoromethylphenyl)-N-(3-pyridy(methyl)-ethylamine.

Similar reaction with B-methoxy-fi-(4-trifluoromethylphenyl)-ethylbromide givesfi-methoxy-B-(4-trifluoromethylphenyl)-N-(3-pyridylmethyl)-ethylamine.

EXAMPLE6 Following the procedure of Example 1, 3-aminoethylpyridine isreacted with l-methoxy-l 3 trifluoromethylphenyl)-2-propyl bromide togive N-(3"- pyridylethyl( l-methoxyl-( 3 -trifluoromethylphenyl)-2-propylamine.

EXAMPLE 7 Ingredients Mg./tablet ethylamine Calcium sulfate, dihydrate65 Sucrose l2 Starch 7 Talc 5 Stearic acid 3 The sucrose, calciumsulfate and active medicament (as the hydrochloride) are thoroughlymixed and granulated with hot 10 percent gelatin solution. The wettedmass is passed through a No. 6 mesh screen directly onto dr 'ngbtrays.The granules are dried at F. and passed throug a o. 20 mesh screen,

mixed with the starch, talc and stearic acid, and compressed intotablets.

EXAMPLE 8 Ingredients fl-methoxy-N-methyl-N- 3-trifluoromethylphenyl)-ethylamine Magnesium stearate Lactose MgJcapsule or a pharmaceuticallyacceptable acid addition salt thereof, in which R is lower alkyl of fromone to three carbon atoms;

R is hydrogen or methyl;

R, is hydrogen or lower alkyl of from one to three carbon atoms; and

A is a lower alkylene chain, straight or branched, of from one to threecarbon atoms.

2. A compound according to claim 1 in which the CF; group is in the metaposition.

3. A compound according to claim 2 in which the pyridine ring is3-substituted.

4. A compound according to claim 3 in which R is methyl.

5. A compound according to claim 4 in which A is methylene.

6. A compound according to claim 5 in which R is hydrogen.

7. A compound according to claim 6 in which R is hydrogen, being thecompound fi-methoxy-B-(Zvtrifluoromethylphenyl)-N-( 3-pyridylmethyl)-ethylamine.

8. A compound according to claim 6 in which R is methyl, being thecompound B-methoxy-N-methyl-N-(3-pyridylmethyl )-B-(3-trifluoromethylphenyl)-ethylamine.

i i l 4 l

2. A compound according to claim 1 in which the CF3 group is in the metaposition.
 3. A compound according to claim 2 in which the pyridine ringis 3-substituted.
 4. A compound according to claim 3 in which R ismethyl.
 5. A compound according to claim 4 in which A is methylene.
 6. Acompound according to claim 5 in which R1 is hydrogen.
 7. A compoundaccording to claim 6 in which R2 is hydrogen, being the compound Beta-methoxy- Beta-(3-trifluoromethylphenyl)-N-(3''-pyridylmethyl)-ethylamine.
 8. Acompound according to claim 6 in which R2 is methyl, being the compoundBeta -methoxy-N-methyl-N-(3''-pyridylmethyl)- Beta-(3-trifluoromethylphenyl)-ethylamine.